Dr. Roger Wagner is an outstanding cardiologist and scientist with a PhD from Caltech who plans to focus his energies on understanding the molecular basis of cardiomyopathy as an academic physician scientist. His research and education at Stanford will broaden his knowledge base and experience with the intricacies of high throughput microarray screening and analysis technologies, physiological models central to cardiovascular research, and advanced molecular biological techniques such as the construction and analysis of knockout mouse disease models in collaboration with experts from each field. In his research, he will investigate the role of new LIM proteins in the development of cardiomyopathies. LIM proteins are important mediators of many aspects of cell specification and function. Many LIM proteins have proven roles in the differentiation, function, and maintenance of phenotype of the cardiovascular system, and a remarkable number are involved in the pathophysiology of cardiomyopathies. The key roles these known LIM proteins play in cardiovascular development, function, and disease suggest that other as yet uncharacterized LIM proteins will be similarly important. This proposal outlines a powerful method of identifying new LIM proteins involved in the pathogenesis of cardiomyopathy through microarray transcription profiling of four mouse models of cardiomyopathy. Preliminary studies have identified four new LIM protein genes whose expression changes radically in a mouse model of hypertrophic cardiomyopathy. The expression and function of these and other new LIM proteins in normal and disease models will be investigated in detail to determine their role in the development of cardiomyopathy. The effect of loss of function of these proteins will be studied through the analysis of knockout mouse models, and it is expected that a number of these knockout animals will have significant defects in their ability to adapt to physiologic stress on the cardiovascular system. This proposal combines the best aspects of the post-genomics era, microarray transcription profiling, mature molecular biological techniques, and well-developed physiologic models of disease to focus on the molecular basis of cardiomyopathy. The insights gained in this research into the pathophysiology of cardiomyopathy will help direct further research and therapeutic interventions for many years to come.